Conformational changes within the HLA‐A1:MAGE‐A1 complex induced by binding of a recombinant antibody fragment with TCR‐like specificity

Abstract

Although there is X-ray crystallographic evidence that the interaction between major histocompatibility complex (MHC, in humans HLA) class I molecules and T cell receptors (TCR) or killer cell Ig-like receptors (KIR) may be accompanied by considerable changes in the conformation of selected residues or even entire loops within TCR or KIR, conformational changes between receptor-bound and -unbound MHC class I molecules of comparable magnitude have not been observed so far. We have previously determined the structure of the MHC class I molecule HLA-A1 bound to a melanoma antigen-encoding gene (MAGE)-A1-derived peptide in complex with a recombinant antibody fragment with TCR-like specificity, Fab-Hyb3. Here, we compare the X-ray structure of HLA-A1:MAGE-A1 with that complexed with Fab-Hyb3 to gain insight into structural changes of the MHC molecule that might be induced by the interaction with the antibody fragment. Apart from the expulsion of several water molecules from the interface, Fab-Hyb3 binding results in major rearrangements (up to 5.5 Å ) of heavy chain residues Arg65, Gln72, Arg145, and Lys146. Residue 65 is frequently and residues 72 and 146 are occasionally involved in TCR binding-induced conformational changes, as revealed by a comparison with MHC class I structures in TCR-liganded and -unliganded forms. On the other hand, residue 145 is subject to a reorientation following engagement of HLA-Cw4 and KIR2DL1. Therefore, conformational changes within the HLA-A1:MAGE-A1:Fab-Hyb3 complex include MHC residues that are also involved in reorientations in complexes with natural ligands, pointing to their central importance for the peptide-dependent recognition of MHC molecules.

Crystal Structure of Swine Major Histocompatibility Complex Class I SLA-1*0401 and Identification of 2009 Pandemic Swine-Origin Influenza A H1N1 Virus Cytotoxic T Lymphocyte Epitope Peptides

“…3D) (61). The PC anchor residues for SLA-1*0401 are similar to those for HLA-A*01, HLA-B*35, and HLA-B*57, which have large residues with an aromatic ring (32,59,61). The aromatic rings in S-OIV NW9 and Ebola AY9 are held in close contact with residues in pocket F by strong hydrogen bonds and van der Waals contacts (Table 4).…”

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

“…3 (A and B) is embedded into conventional twodimensional images and was created using the Adobe Acrobat 3D Toolkit and Adobe Acrobat software. We have recently described the procedure to generate such images (49,50), starting from raw Protein Data Bank files (3BXN, 3BVN, 3BP4, 1UXS, 3BP7, and 1UXW).…”

Dynamical Characterization of Two Differentially Disease Associated MHC Class I Proteins in Complex with Viral and Self-Peptides

“…Comparative X-ray crystallographic studies of free and receptor-bound pMHC indicated that peptide residues, in particular, exhibit flexibility, 8 but plasticity was recently also observed for HC residues belonging to helical regions of the binding groove, based on structural and infrared (IR) spectroscopic studies. [9][10][11][12][13] Consequently, an intrinsic peptide sequence-independent and conformationindependent flexibility (i.e., a flexibility that is not evident from crystal structures) of pMHC complexes has been proposed as an essential feature for its recognition by cellular ligands, 9,11,14 suggesting an additional level of complexity for pMHC-TCR interactions and adding to the difficulty of understanding the phenomenon of T-cell crossreactivity. 15 Many of the studies focusing on the characteristics of pMHC complexes were carried out with the human HLA-A2 and HLA-B27 antigens.…”